The present invention relates to controlled release unit dose formulations of water soluble drugs in general which are exemplified by diltiazem hydrochloride (diltiazem). There is a need for a means for varying the release rates of water soluble drugs from multiparticulate beads which have release membranes that are applied by a coating process. Diltiazem is sold commercially in extended release pharmaceutical dosage forms in order to maintain a therapeutic serum level of diltiazem and to minimize the effects of missed doses of drugs caused by a lack of patient compliance. The minimum therapeutic plasma diltiazem concentrations are in the range of 50 to 200 ng/ml.
Cardizem.RTM. CD is described as a once-a-day extended release capsule containing diltiazem and fumaric acid. In the file history of U.S. Pat. No. 5,286,497, representations were made that the formulation disclosed in that patent is the formulation for Cardizem.RTM. CD. The formulation for Cardizem.RTM. CD is identified in the file history of U.S. Pat. No. 5,286,497 as having a "stair-step release profile" which has a rapid release bead and an extended release bead.
U.S. Pat. No. 5,567,441 also discloses a formulation of diltiazem which is bioequivalent to Cardizem.RTM. CD but has a different release profile in hydrochloric acid. That formulation exhibits a slower in vitro release profile in 0.1N hydrochloric acid than the slow release bead of the present invention but exhibits substantially the same in vivo release profile.
In U.S. Pat. No. 5,229,135 and in U.S. Pat. No. 5,529,791, once-a-day formulations are described that are based on a single pellet which is prepared with an active core which is coated with diltiazem and an inner and outer membrane. Other diltiazem formulations are disclosed in U.S. Pat. No. 4,721,619; U.S. Pat. No. 4,894,240; U.S. Pat. No. 5,002,776; U.S. Pat. Nos. 5,364,620; 4,891,230; U.S. Pat. No. 4,917,899; U.S. Pat. No. 5,288,505; and U.S. Pat. No. 5,336,504.
The present invention provides novel water soluble pharmaceutical formulations which are two-pellet based capsule formulations. The diltiazem formulations made according to the present invention do not have a "stair-step release profile" but do provide a "two- peak pharmacokinetic profile". Moreover, the diltiazem formulations of the present invention does not require the presence of fumaric acid or any other organic acid in the core. The present invention also provides a means for varying the release rates of water soluble to allow for faster in vitro release of the drug.